Astrocytes have long been appreciated as an essential cell type in the central nervous system, due to their trophic, metabolic, and physical support of the neurons. However, data are accumulating that astrocytes are also important modulators of neuronal function, regulating dendritic spine architecture and synaptic strength. In addition, astrocytes are integral to the initiation and progression of several neurodegenerative diseases, including ALS and Parkinsons disease. The Mandel Lab has recently found that astrocytes play a key role in the behavioral progression of Rett syndrome, a neurodevelopmental disease caused by mutations in the gene coding methyl-CpG binding protein 2 (MeCP2). These results run counter to the prevailing hypothesis of this disease as one of solely neuronal origin, and subsequently almost no data has been generated on the fundamental properties of astrocytes that lack MeCP2. Therefore the goal of this research is to determine the morphological and functional consequences of MeCP2 deletion in astrocytes, in order to understand the mechanism by which they influence Rett syndrome behaviors. Because the behavioral changes caused by MeCP2 loss in astrocytes must be transduced by neurons, the proposed project will focus on the capacity of astrocytes to signal to neurons with secreted gliotransmitters and to regulate the outgrowth of dendrites and synaptic formation. Because MeCP2 is a regulator of transcription, this work will also provide insights into the regulation of genes necessary for the intercommunication between astrocytes and neurons, of which little is known. These studies will also entail training and the development of new skills and expertise in general neuroscience, neuroanatomy, genetics, biochemistry, primary culture techniques, and live imaging using confocal microscopy. PUBLIC HEALTH RELEVANCE: Rett syndrome is a neurodevelopmental disease that affects 1 in 15,000 female births. Studies on mouse models of Rett syndrome have focused almost entirely on neurons, yet recent research has shown that astrocytes contribute significantly to numerous Rett symptoms. Astrocytes make up >50% of the cells in the brain and have been shown to influence numerous normal and pathological processes. The proposed project will attempt to determine the mechanisms of the astrocytic contribution to Rett syndrome, which may lead to new therapeutic strategies and novel insights into the intercommunication between astrocytes and neurons.